Glucagon was discovered in 1923, two years after the discovery of insulin. Chemically unrelated to insulin, glucagon is a single-chain polypeptide hormone containing 29 amino acid residues and having a molecular weight of nearly 3500. In contrast to insulin, glucagon contains no cysteine and, consequently, no disulfide linkages. The structure of human glucagon is identical to porcine, bovine, and rat glucagon and many current glucagon preparations are extracted from beef and pork pancreas.
Glucagon secretion, like that of insulin, is controlled by the interplay of gastrointestinal food products, hormones, and other factors. Glucagon is secreted from pancreatic .alpha.-cells in response to stimuli which include (i) falling blood glucose levels, (ii) the physiological increments in amino acids which follow a protein meal, (iii) vigorous exercise, (iv) starvation, and (v) hypoglycemia. It was discovered as a hyperglycemic factor, present in pancreatic extracts, which stimulated hepatic glycogenolysis (the so-called `hyperglycemic glycogenolytic factor`). Glucagon is reported to exert major effects on liver glucose metabolism to increase hepatic glucose production, at least through cAMP-mediated actions, which are exerted both directly, to release glucose from glycogen through stimulation of glycogenolysis, and indirectly, through inhibition of glycogen synthesis. During relative hypoinsulinemia, glucagon can also stimulate gluconeogenesis. Glucagon is not considered to exert physiologically significant effects on carbohydrate metabolism in muscle.
Glucose is physiologically the most important regulator of glucagon. A rise in plasma glucose concentration leads to an inhibition of glucagon secretion and vice versa. Unger, R. H. and Orci, L., "Glucagon and the A Cell," N. Eng. J. Med. 304:1518-1524 and 1575-1580 (1981). Both insulin and somatostatin inhibit the secretion of glucagon.
The role of glucagon and, in general, its actions are reported to be antagonistic to those of insulin. Insulin serves as a hormone of fuel storage while glucagon is reported to serve as a hormone of fuel mobilization. Following a carbohydrate meal, pancreatic .beta.-cells secrete insulin and pancreatic .alpha.-cell secretion of glucagon is suppressed; this allows cells to store fuels such as glucose in liver, muscle, and adipose tissue. Conversely, during starvation, stimulation of glucagon secretion and suppression of insulin secretion direct breakdown and efficient utilization of fuels stored intracellularly, initially liver glycogen, and subsequently adipose tissue fat, to meet the energy needs of the brain and other tissues. A regulated role for glucagon as the hormone of injury and insult (catabolic illness) has been proposed. For example, impaired glucose tolerance and hyperglycemia noted with infection are associated with increased concentrations of plasma glucagon. Similar increases are seen in patients with myocardial infarctions, burns, and after major trauma. In these situations, glucagon is said to stimulate gluconeogenesis and provide the glucose needed under conditions of insult.
Glucagon, therefore, has generally accepted physiological roles as a counterregulatory (anti-hypoglycemic) hormone, and a major regulator of fuel metabolism during starvation. Because of its effect to increase blood glucose levels in individuals with extant hepatic glycogen stores, glucagon is widely used clinically in the acute management of severe hypoglycemia complicating insulin replacement therapy of insulin-dependent (type 1) diabetes mellitus. Glucagon is particularly useful in the treatment of insulin-induced hypoglycemia when dextrose (glucose) solution is not available or, for example, when a patient is convulsing or recalcitrant and intravenous glucose cannot be administered. Glucagon is effective in small doses, and no evidence of toxicity has been reported with its use.
When given, glucagon may be administered intravenously, intramuscularly, or subcutaneously, typically in a dose of 1 milligram. Once glucagon is introduced for hypoglycemic coma induced by either insulin or oral hypoglycemic agents, a return to consciousness should be observed within 20 minutes; otherwise, intravenous glucose must be administered as soon as possible. Goodman and Gillman's The Pharmacolooic Basis of Theraueutics, p. 1510-1512 (7th Ed. 1985).
Hypoglycemic reactions may occur in any diabetic subject treated with insulin or with an oral hypoglycemic agent. Reactions are frequently seen in the labile form of the disease, a form characterized by unpredictable spontaneous reductions in insulin requirement. In other instances, precipitating causes are responsible, such as a failure to eat, unaccustomed exercise, and inadvertent administration of too large a dose of insulin. Frequently, however, there is no discernible cause. When the rate of fall in blood glucose is rapid, the early symptoms are those brought on by the compensating secretion of epinephrine, which includes sweating, weakness, hunger, tachycardia, and "inner trembling." When the concentration of glucose falls slowly, the symptoms and signs are primarily related to the brain and include headache, blurred vision, diplopia, mental confusion, incoherent speech, coma, and convulsions. If the fall in blood glucose is rapid, profound, and persistent, all such symptoms may be present.
The majority of the signs and symptoms of insulin hypoglycemia are the results of functional abnormalities of the central nervous system, since hypoglycemia deprives the brain of the substrate (glucose) upon which it is almost exclusively dependent for its oxidative metabolism. During insulin coma, oxygen consumption in human brain decreases by nearly half. The reduction in glucose consumption is disproportionately greater, which indicates that the brain is utilizing other substrates. After prolonged fasting in man the brain adapts, and the bulk of the fuel utilized is made up of ketone bodies. A prolonged period of hypoglycemia causes irreversible damage to the brain. Goodman and Gillman's The Pharmacologic Basis of Therapeutics, p. 1502-1503 (7th Ed. 1985).
The symptoms of hypoglycemia yield almost immediately to the intravenous injection of glucose unless hypoglycemia has been sufficiently prolonged to induce organic changes in the brain. If the patient is not able to take a soluble carbohydrate or a sugar-containing liquid such as fruit juice orally and if glucose is not available for intravenous injection, glucagon may be given. It will be understood, however, that the utility of glucagon in treating hypoglycemia is limited by its inaction or ineffectiveness in patients with depleted liver glycogen stores. Since glucagon acts only on liver (but not on skeletal muscle) glycogen by converting it to glucose, it has no therapeutically useful hyperglycemic effect in patients with depleted liver glycogen, a condition which cannot be determined in the fitting patient. Thus, in the convulsing or comatose patient, glucagon treatment will not alleviate hypoglycemia if the patient has no or insufficient liver glycogen to be mobilized. In addition to states of starvation, it is also understood that glucagon is of little or no help in other states in which liver glycogen is depleted such as adrenal insufficiency or chronic hypoglycemia. Normally, then, intravenous glucose must be given if the patient fails to respond to glucagon.